POS0637 USING THE “POTENTIAL-OUTCOMES FRAMEWORK” TO PREDICT ADDED VALUE OF MORE INTENSIVE INITIAL THERAPY FOR INDIVIDUAL EARLY RA PATIENTS
Authors: S. Fadaei, P. Welsing, J. Spierings
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> DMARDs are the cornerstone of early RA treatment with Methotrexate (MTX) typically used as a first line treatment. More intensive initial combination therapy has been evaluated in clinical trials showing limited added value with longer follow-up in a treat-to-target (T2T) strategy [1,2]. Such studies report the treatment effect on group level, however, precision medicine requires information on which individuals will respond relevantly better to a more intensive therapy compared to MTX. <h3>Objectives</h3> The aim of this study was to identify whether clinically relevant heterogeneity in treatment effect exist, utilizing a "potential-outcomes framework" approach and to explore whether individual added value of more intensive therapy can be predicted. <h3>Methods</h3> We used data from U-Act-Early. This RCT compared initiating MTX monotherapy, tocilizumab (TCZ), and MTX + TCZ treatment in a T2T strategy in early RA with monthly disease activity assessment [1]. Time averaged CDAI score over 6 months was the primary endpoint. As physician VAS was missing a previously reported modified (m) CDAI was used [2]. Time-averaged mCDAI over 24 months and DAS28 over 6/24 months were secondary outcomes. For each patient we predicted outcomes of the treatments that they were not allocated to using multiple imputation (150 imputations using a random forest method). Predicted Individual Treatment effects (PITE) for each treatment comparison were calculated and the variation in PITEs between patients was evaluated. We used logistic regression to predict added value of more intensive treatment. <h3>Results</h3> Figure 1A shows the average PITE for TCZ + MTX versus MTX monotherapy as initial treatment over 6 months. 134 of 299 patients (45%) would relevantly benefit from MTX + TCZ (green part Figure 1). We defined sufficient added value for an individual patient as Cohen's effect size ≥0.8. Added value of MTX + TCZ could be predicted to a limited extent with the same variables used for imputation (AUC-ROC 0.65 (95% CI 0.56-0.73); Table 1 and Figure 1B). At 24 months 36% could be defined as benefitting from more intensive initial treatment. When using DAS28 as outcome measure 87% and 82% of patients benefitted respectively at 6 and 24 months. Added value could also be predicted to a limited extent (AUC-ROC 0.63 (0.54-0.71); 0.66 (0.56-0.75) and 0.63 (0.54-0.71) respectively) using logistic regression. <h3>Conclusion</h3> Relevant added value of more intense initial treatment for individual early RA patients could be defined and predicted to some extent using clinical predictors. However, thresholds for relevant clinical benefit as well as prediction should be improved and validated. <h3>References</h3> [1]Bijlsma JWJ, Welsing PMJ, Woodworth TG, Middelink LM, Pethö-Schramm A, Bernasconi C, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. The Lancet. 2016;388(10042):343–55. [2]Verhoeven MMA, de Hair MJH, Tekstra J, Bijlsma JWJ, van Laar JM, Pethoe-Schramm A, et al. Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-I. Ann Rheum Dis. 2019 Oct 1;78(10):1333 LP – 1338. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.